Approximately 120 million individuals are infected with Schistosoma haematobium in sub-Saharan African alone. S. haematobium adult worms, the causative agent of urogenital schistosomiasis, lay eggs throughout the urogenital tract. These eggs induce a pronounced inflammatory response responsible for the human morbidity and mortality associated with infection. To date very little is known about how S. haematobium is able to induce such a robust immune response while evading immune clearance and immunity in many individuals. This lack of knowledge is due to the historical lack of both a model for S. haematobium egg- associated pathology, and genetic tools for manipulation of the S. haematobium parasite. Building on recent advances in the S. haematobium field, this collaborative proposal employs the first published mouse model of S. haematobium induced bladder pathology (generated by the PI), and the first successful approaches for genetic manipulation of S. haemtobium (pioneered by the co-investigators). The experiments proposed will explore the functions of the S. haematobium homolog of the parasite egg- secreted immunomodulatory protein IPSE. IPSE was originally described in S. mansoni, the sister species of schistosome responsible for hepatoenteric schistosomiasis. IPSE is the most abundant S. mansoni egg secreted protein, and has numerous published biochemical functions, many of which were first described by a co-investigator on this proposal. Our collaborative team across four institutions will first define the biochemical functions of the S. haematobium IPSE homologue. We will then generate genetically modified S. haematobium strains with deficient IPSE gene expression to determine the effects of IPSE in vivo. Achievement of the aims of this proposal would represent key milestones for S. haematobium research, including, to our knowledge, the first studies on S. haematobium-derived immunomodulatory proteins and the first use of transgenic S. haematobium strains to determine the function of an S. haematobium protein in vivo.